Abstract Aging, a major risk factor for both Alzheimer?s disease (AD) and cancer, is characterized by an oxidative redox shift, decreased redox buffer protection, and increased free radical reactive oxygen species (ROS) generation, likely linked to progressive mitochondrial dysfunction. Studies show that while the incidence of lung and prostate cancer are not different between AD and age-matched controls, the prevalence of pancreatic cancer (PC) in AD is 6.7-fold that of controls; however, this finding and possible role of AD and/or underlying genetic risk have not been described. These findings suggest an association of redox imbalance with the progression of both AD and PC, leading us to consider whether common roots are shared between AD and cancer etiology that may involve dysregulation of NADK and allied pathways resulting in increased levels of reactive oxygen species (which the parent CA award has instantiated in cancer) and may be manifested as either cancer or AD in a cell-intrinsic manner, potentially dependent on NADK variants in the population. We propose to leverage the existing tools/models developed in the parent R01 to conduct a comparison of NADK-associated cancer to potential NADK-associated AD. This hypothesis is significant in testing how specific allelic differences in enzymes, like NADK that regulate redox metabolic control/balance, may underlie why an individual may develop one type of disease (e.g., cancer) versus another (e.g., AD), or perhaps both. We propose that AD and PC share both aging and redox imbalance as primary risk factors that impact the onset and progression of both diseases. Dysregulation of NADK (causing increased or reduced oxidative stress) and its allied pathways may manifest as cancer, protection against cancer, or AD in a cell-intrinsic manner, potentially dependent on NADK variants that exist in the population. To explore the possible role for NADK and NAD+ in the mitigation of ROS and potential contribution to age of onset and/or progression of AD we will (1) Generate and characterize AD mouse models lacking Nadk to investigate the role of NADPH and ROS in the onset and progression of AD, creating a platform to study possible contributions of NADK, NADPH and ROS to onset of AD. (2) Query human genome sequencing data to define human variation in NADK and characterize naturally occurring variants to determine pathogenicity to assess impact on NADK function, NADPH generation, and ROS production in our defined cellular NADK assays. (3) Assess the metabolic impact of impaired or reduced NADK function by using untargeted metabolomics as an unbiased mechanism to identify NADK-associated pathways within and outside of ROS for an assessment of the broader metabolic alterations caused by reduced functional NADK. The data generated by these studies will improve our understanding of the impact of reactive oxygen species on the onset and progression of Alzheimer?s disease, define role(s) for NADK and NAD+ in this process, identify natural human variation that may contribute to AD onset and progression, and explore metabolomic signatures related to poor or altered NADK function.